PROJECT SUMMARY/ABSTRACT Autoimmune diseases are chronic inflammatory diseases of unknown etiology that results from the combination of genetic susceptibility, environmental factors, and immune dysregulation. There are more than 80 human diseases currently classified as autoimmune, including multiple sclerosis, inflammatory bowel diseases, type 1 diabetes mellitus, rheumatoid arthritis, and systemic lupus erythematosus. Since they affect up to 8% of the US population and often attack young adults, especially women, their social and economic impact is enormous. Immunosuppressive drugs are classical therapies to treat a wide range of autoimmune diseases. However, the treatment of autoimmune diseases has been based on non-selective immunosuppressants or cytotoxic drugs that in general offer a limited clinical efficacy. Even more selective immunosuppressive drugs such as cyclosporine A and FK506 possess serious side effects, including acute neurological toxicity and chronic nephrotoxicity. Biologicals are expensive and some patients do not respond to them adequately. Thus, efforts must be made to identify new immunomodulatory agents that are effective through a novel mechanism to circumvent existing side effects and more selective to reduce off-target effects. Subglutinols A and B are ?-pyrone diterpenoid natural products with a novel chemical scaffold. They showed potent immunosuppressive activity comparable to that of cyclosporine A. We reported the first total synthesis of subglutinols A and B and demonstrated that they show multimodal immune-suppressive effects on activated T cells and possess a significant therapeutic window. We further revealed that subglutinols might exert their anti-inflammatory effects by affecting T cell metabolism which has been yet to be explored as an autoimmune disease target. All together, our data suggests that subglutinols A and B may have great potential for safe immunosuppressive therapeutics for autoimmune diseases with a novel and unique mode of action. The objective of this proposal is to identify the molecular target(s) of subglutinols to establish their mode of action and to develop subglutinol-derived chemical probes to study the regulation mechanism of immune responses through the following specific aims: (1) Identify the molecular target(s) and mode of action of sublutinols and (2) Determine the key pharmacophores of subglutinols. If successful, such therapeutics and drug targets are expected to be useful for the treatment of autoimmune diseases and for post-transplantation care, thus resulting in a sustained remission of the disease and better patient outcome.